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Cytoplasmic accumulation of FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and defects in inhibitory synapses

Jelena Scekic-Zahirovic, Inmaculada Sanjuan-Ruiz, Vanessa Kan, Salim Megat, Pierre De Rossi, Stéphane Dieterlé, Raphaelle Cassel, Pascal Kessler, Diana Wiesner, Laura Tzeplaeff, Valérie Demais, Hans-Peter Muller, Gina Picchiarelli, Nibha Mishra, Sylvie Dirrig-Grosch, Jan Kassubek, Volker Rasche, Albert Ludolph, Anne-Laurence Boutillier, Magdalini Polymenidou, Clotilde Lagier-Tourenne, Sabine Liebscher, Luc Dupuis
doi: https://doi.org/10.1101/2020.06.09.141556
Jelena Scekic-Zahirovic
1Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Strasbourg, France
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Inmaculada Sanjuan-Ruiz
1Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Strasbourg, France
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Vanessa Kan
2Institute of Clinical Neuroimmunology, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich. Germany
3BioMedical Center, Medical Faculty, Ludwig-Maximilians-University Munich, Munich, Germany
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Salim Megat
1Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Strasbourg, France
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Pierre De Rossi
4Department of Quantitative Biomedicine, University of Zurich
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Stéphane Dieterlé
1Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Strasbourg, France
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Raphaelle Cassel
1Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Strasbourg, France
5Université de Strasbourg, UMR 7364 CNRS, Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), Strasbourg, France
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Pascal Kessler
6Université de Strasbourg, Inserm, Unité mixte de service du CRBS, UMS 038, Strasbourg, France
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Diana Wiesner
7Department of Neurology, University of Ulm
8Deutsches Zentrum für Neurodegenerative Erkrankungen, Ulm
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Laura Tzeplaeff
5Université de Strasbourg, UMR 7364 CNRS, Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), Strasbourg, France
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Valérie Demais
9Plateforme Imagerie In Vitro, CNRS UPS-3156, NeuroPôle, Strasbourg, France
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Hans-Peter Muller
7Department of Neurology, University of Ulm
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Gina Picchiarelli
1Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Strasbourg, France
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Nibha Mishra
10Department of Neurology, The Sean M. Healey and AMG Center for ALS at Mass General, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
11Broad Institute of Harvard University and MIT, Cambridge, MA, USA
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Sylvie Dirrig-Grosch
1Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Strasbourg, France
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Jan Kassubek
7Department of Neurology, University of Ulm
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Volker Rasche
7Department of Neurology, University of Ulm
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Albert Ludolph
7Department of Neurology, University of Ulm
8Deutsches Zentrum für Neurodegenerative Erkrankungen, Ulm
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Anne-Laurence Boutillier
5Université de Strasbourg, UMR 7364 CNRS, Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), Strasbourg, France
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Magdalini Polymenidou
4Department of Quantitative Biomedicine, University of Zurich
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Clotilde Lagier-Tourenne
10Department of Neurology, The Sean M. Healey and AMG Center for ALS at Mass General, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
11Broad Institute of Harvard University and MIT, Cambridge, MA, USA
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Sabine Liebscher
2Institute of Clinical Neuroimmunology, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich. Germany
3BioMedical Center, Medical Faculty, Ludwig-Maximilians-University Munich, Munich, Germany
12Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
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  • For correspondence: ldupuis@unistra.fr sabine.liebscher@med.uni-muenchen.de
Luc Dupuis
1Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, UMR-S1118, Strasbourg, France
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  • For correspondence: ldupuis@unistra.fr sabine.liebscher@med.uni-muenchen.de
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Abstract

Gene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS, lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives behavioral abnormalities in knock-in mice, including locomotor hyperactivity and alterations in social interactions, in the absence of widespread neuronal loss. Mechanistically, we identified a profound increase in neuronal activity in the frontal cortex of Fus knock-in mice in vivo. Importantly, RNAseq analysis suggested involvement of defects in inhibitory neurons, that was confirmed by ultrastructural and morphological defects of inhibitory synapses and increased synaptosomal levels of mRNAs involved in inhibitory neurotransmission. Thus, cytoplasmic FUS triggers inhibitory synaptic deficits, leading to increased neuronal activity and behavioral phenotypes. FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, but also in other neurodegenerative diseases with FUS mislocalization.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* shared first authors

  • Funding This work was funded by Agence Nationale de la Recherche (ANR-16-CE92-0031 to ALB and LD, ANR-16-CE16-0015 to LD), by Fondation pour la recherche médicale (FRM, DEQ20180339179), Axa Research Funds (rare diseases award 2019, to LD), Fondation Thierry Latran (HypmotALS, to LD), MNDA (Dupuis/Apr16/852-791 to LD), ALSA (2235, 3209 and 8075 to LD and CLT), Target ALS (to CLT), Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology - EXC 2145 SyNergy - ID 390857198 (SL), the DFG, Emmy Noether Programme (SL), the Deutsche Gesellschaft für Muskelkranke (SL) and the Graduate School for Systemic Neurosciences GSN-LMU (ZG, VK). CLT is the recipient of the Araminta Broch-Healey Endowed Chair in ALS. The collaborative work between LD and MP laboratories was funded by ARSLA (2016). ISR was funded by the Région Grand Est (France).

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Cytoplasmic accumulation of FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and defects in inhibitory synapses
Jelena Scekic-Zahirovic, Inmaculada Sanjuan-Ruiz, Vanessa Kan, Salim Megat, Pierre De Rossi, Stéphane Dieterlé, Raphaelle Cassel, Pascal Kessler, Diana Wiesner, Laura Tzeplaeff, Valérie Demais, Hans-Peter Muller, Gina Picchiarelli, Nibha Mishra, Sylvie Dirrig-Grosch, Jan Kassubek, Volker Rasche, Albert Ludolph, Anne-Laurence Boutillier, Magdalini Polymenidou, Clotilde Lagier-Tourenne, Sabine Liebscher, Luc Dupuis
bioRxiv 2020.06.09.141556; doi: https://doi.org/10.1101/2020.06.09.141556
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Cytoplasmic accumulation of FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and defects in inhibitory synapses
Jelena Scekic-Zahirovic, Inmaculada Sanjuan-Ruiz, Vanessa Kan, Salim Megat, Pierre De Rossi, Stéphane Dieterlé, Raphaelle Cassel, Pascal Kessler, Diana Wiesner, Laura Tzeplaeff, Valérie Demais, Hans-Peter Muller, Gina Picchiarelli, Nibha Mishra, Sylvie Dirrig-Grosch, Jan Kassubek, Volker Rasche, Albert Ludolph, Anne-Laurence Boutillier, Magdalini Polymenidou, Clotilde Lagier-Tourenne, Sabine Liebscher, Luc Dupuis
bioRxiv 2020.06.09.141556; doi: https://doi.org/10.1101/2020.06.09.141556

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